Abstract
Neutrophil infiltration plays an important role in the initial phase of hepatic ischemia and reperfusion injury (HIRI). Despite many different key molecules that have been reported to meditate neutrophil trafficking in HIRI, the mechanism of this process has not been fully elucidated. In this study, we found that Carabin deficiency in myeloid cells (LysMCre : Carabinfl/fl) aggravated IRI-induced hepatic injury and apoptosis through increasing the infiltration of CD11b+Ly6G+ neutrophils. ImmGen Datasets further revealed that Carabin was expressed in bone marrow neutrophils (GM.BM) but was significantly downregulated in thio-induced peripheral neutrophils (GN.Thio.PC), which was consistently verified by comparing GM.BM and liver-infiltrating neutrophils induced by IRI. Mechanistically, up-regulation of Carabin in GM.BM in vitro reduced the expression levels of P-selectin, E-selectin, and αvβ3 integrin through inhibiting Ras-ERK and Calcineurin-NFAT signaling. Furthermore, blocking P-selectin, E-selectin, and αvβ3 integrin in LysMCre : Carabinfl/fl mice decreased the frequency and number of CD11b+Ly6G+ neutrophils and reversed hepatic ischemia−reperfusion damage. In conclusion, our results provide a new understanding of Carabin, such that it is expressed and functions not only in adaptive immune cells (T and B cells) but also in innate immune cells (neutrophils), contributing to the migration of neutrophils. These findings provide novel and promising therapeutic targets for the prevention of HIRI during liver transplantation or hepatic surgery.
Highlights
Hepatic ischemia and reperfusion injury (HIRI) mainly results from liver transplantation, liver surgical resection, and hemodynamic shock [1, 2]
We found that serum ALT levels were significantly increased in LysMCre : Carabinfl/fl mice compared with those in LysMCre mice (Figures 1B, C)
To further determine the critical role of Carabin in liver injury, we performed hematoxylin and eosin (H&E) staining of liver tissue with different mice and revealed that hepatocyte necrosis in LysMCre : Carabinfl/fl mice was markedly severe in LysMCre mice (Figure 1D)
Summary
Hepatic ischemia and reperfusion injury (HIRI) mainly results from liver transplantation, liver surgical resection, and hemodynamic shock [1, 2]. The shift from ischemia to reperfusion is generally considered to Carabin Prevents Neutrophil Trafficking be the main factor leading to liver injury [5, 6]. Subsequent reperfusion triggers a cascade of events, including the activation and recruitment of innate and adaptive immune cells, as well as significant liver injury [7]. Carabin has been reported to be a novel negative regulator of B-cell function in systemic lupus erythematosus (SLE) and B-cell lymphoma through inhibiting the crosstalk between BCR and TLR9 pathways [11, 12]. These studies have demonstrated that Carabin is a key regulator involved in the activation of adaptive immune cells. Its role and underlying mechanisms in innate immune cells remain poorly understood
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